The aim of this study is to identify the most effective thermal predictor of heat-related very-elderly mortality in two cities located in different geographical contexts of central Italy. We tested the hypothesis that use of the state-of-the-art rational thermal indices, the Universal Thermal Climate Index (UTCI), might provide an improvement in predicting heat-related mortality with respect to other predictors. Data regarding very elderly people (≥ 75 years) who died in inland and coastal cities from 2006 to 2008 (May-October) and meteorological and air pollution were obtained from the regional mortality and environmental archives. Rational (UTCI) and direct thermal indices represented by a set of bivariate/multivariate apparent temperature indices were assessed. Correlation analyses and generalized additive models were applied. The Akaike weights were used for the best model selection. Direct multivariate indices showed the highest correlations with UTCI and were also selected as the best thermal predictors of heat-related mortality for both inland and coastal cities. Conversely, the UTCI was never identified as the best thermal predictor. The use of direct multivariate indices, which also account for the extra effect of wind speed and/or solar radiation, revealed the best fitting with all-cause, very-elderly mortality attributable to heat stress.